The UW's Indigenous Wellness Research Institute (IWRI) has successfully pursued its mission to address American Indian and Alaska Native (AIAN) health and eliminate health disparities by developing a trans-disciplinary research infrastructure, cultivating extensive partnerships with leading national and international tribal communities and organizations, and securing $14 million in research and training awards over its initial five years. The UW and School of Social Work have provided fertile ground for IWRI development and have pledged considerable additional institutional and administrative support. This application, in response to RFA-MD-11-003 NIMHD Comprehensive Centers of Excellence (P60) is designed to develop IWRI as a National Comprehensive Center of Excellence (COE) devoted to AIAN health and health disparities research and to develop a cadre of NIH-funded AIAN behavioral scientists. It provides an excellent opportunity for IWRI to consolidate its burgeoning infrastructure and strengthen existing partners into a vibrant, synergistic, collaborative whole. IWRI's thematic focus is on behaviorally rooted health conditions that disproportionately affect AIANS (e.g., cardiovascular disease, obesity, diabetes, HIV/AIDS, substance abuse, and mental illness) and is grounded in the theoretical and empirical work of IWRI's eminent leaders, who have been awarded numerous NIH grants on AIAN health-related projects over the last two decades and, along with the extensive network of IWRI investigators and community partners, have been at the forefront of AIAN behavioral research. Their innovative work emphasizes the importance of historical context in addressing AIAN health needs, as well as the co-occurring factors of violence, substance use, and psychological distress that affect health. These risk factors are conceptualized in the Director's ground-breaking Indigenist Stress-Coping Model, which will be used to guide curriculum and program development. Consistent with the four main objectives of NIMHD Centers, the proposed aims of IWRI are to Improve AIAN health and eliminate health disparities by: (1) developing an integrated, comprehensive, and centralized trans-disciplinary research infrastructure that builds on the successes of IWRI's research, training activities, and community capacity building; (2) cultivating existing and establishing novel partnerships with AIAN tribal communities and other organizations to facilitate truly collaborative research; (3) developing new and enhancing existing research training activities at IWRI that prepare researchers to conduct scientifically rigorous and culturally grounded health research; and (4) strengthening and consolidating AIAN engagement, outreach and institutional partnerships.